SUMMARY Alzheimer?s Disease (AD) progresses slowly and involves many molecular pathways. In addition to accumulation of A plaques and Tau neurofibrillary tangles, there are also inflammatory, vascular and metabolic changes. Human genetic studies of late onset AD (LOAD) risk have identified two major groups of genes, one related to brain inflammation and another with established roles in the endolysosomal pathway. Endolysosomal organelles are utilized by cells to take up, degrade and remove substances from both inside and outside of the cell. The general principles of endolysosomal regulation/dysregulation in AD are not well understood. However, an endolysosomal pathway role is not specific to AD amongst degenerative dementias. In the related condition of Fronto-Temporal Dementia, Progranulin and TMEM106B proteins play key roles, and are linked to the endolysosomal pathway. Here, we seek to leverage knowledge of this FTLD-TDP pathway to understand and modify endolysosomal function in AD and in Tauopathy. Our studies of mice lacking Progranulin suggest that this endolysosomal protein has a pronounced effect on Tau-dependent neuro-degeneration. In Preliminary studies, Tau transgene induced phenotypes are fully rescued by loss of Progranulin. In proposed work, we will characterize this exciting finding with regard to the molecular and cellular details of Tau aggregation, phosphorylation, spreading, metabolism and toxicity. These studies will define a role of Progranulin-dependent regulation of endolysosomes in Tauopathies, including AD. Loss of a second endolysosomal protein, TMEM106B, counteracts loss of Progranulin in certain settings, but not others. For Tauopathy and AD, we will test whether reducing TMEM106B function worsens pathophysiology, and if increasing TMEM106B mimics the loss of Progranulin to rescue Tauopathy. The long-term goal is to define a neuro-degeneration-related endolysosomal pathway that can be targeted to provide disease-modifying therapy for Tauopathies, including Alzheimer?s Disease.